Clinical Neuroscience 4:295-301(1997)
Clinical Spectrum of Leber's Hereditary Optic Neuropathy
John B. Kerrison and Nancy J. Newman
^ Leber's hereditary optic neuropathy (LHON) is a bilateral subacute optic neuropathy caused by mutations in the mitochondrial genome. Primary mutations are located at nucleotide positions 3460, 11778, and 14484 in genes encoding subunits of Complex I of the respiratory chain. Molecular diagnosis has expanded the spectrum of the LHON phenotype and prompted investigation into optic neuropathies due to demyelinating disease, glaucoma, tobacco/alcohol amblyopia, and nutritional optic neuropathy. While mitochondrial mutations are for LHON disease expression, other genetic or epigenetic factors must play a role in disease penetrance and expression. Prodeterminants of disease include heteroplasmy, an X-linked vision susceptibility locus, environmental factors, and secondary mitochondrial mutations.
Clinical Neuroscience 4:295-301, 1997. 1997 Copyright: Wiley-Liss, Inc.
hereditary optic neuropathy; optic nerve; Leber; heteroplasmy; mitochondria
^ The discovery that Leber's hereditary optic neuropathy (LHON) segregated in a nonmendelian, maternal pattern [van Senus 1963] [Erickson 1972] [Wallace et al 1970] [Nikoskelainen et al 1987] suggested a disorder of mitochondrial inheritance [Nikoskelainen et al 1984a] [Egger and Wilson 1983]. Using a candidate approach, Wallace and coworkers screened the mitochondrial genome from several LHON pedigrees and discovered a point mutation at nucleotide position 11778 responsible for the majority of cases [Wallace et al 1988] [Singh et al 1989]. The discovery of the molecular basis of LHON has provided insights into the heterogeneous clinical spectrum of disease that may result. Furthermore, it is evident that other determinants. whether genetic or epigenetic, play a role in disease penetrance and expression. The advent of molecular diagnosis has prompted investigation into the role of mitochondrial DNA (mtDNA) mutations in optic neuropathies due to demyelinating disease, glaucoma, and malnutrition. The purpose of this paper is to review clinical and pathologic features of LHON, the application of mtDNA testing to patients with optic neuropathies other than LHON, and the potential influences on disease penetrance.
^ Mitochondrial mutations found in LHON patients, considered to be of principle importance in disease pathogenesis, must alter an evolutionarily conserved amino acid and be absent in controls [Wallace et al 1988] [Howell et al 1991a]]. Three missense mutations at nucleotide positions 3460 [Huoponen et al 1991] [Howell et al 1991a], 11778 [Wallace et al 1988], and 14484 [Johns et al 1992a] involving NADH dehydrogenase (ND) subunits 1, 4, and 6, respectively, of Complex I, fulfill these criteria and account for 85-90% of mutations worldwide [Howell et al 1994a] [Newman 1997]. In one study, no primary mutation was found in 21% of affected individuals from Finland [Nikoskelainen et al 1996]. The 11778 mutation is responsible for 31-89% of LHON pedigrees in Europe, North America, and Australia and 90% of LHON pedigrees in Japan. The 3460 and 14484 mutations each account for approximately 10-15% of cases. Clinical manifestations of LHON with reference to each of these mutations have been reported [Newman et al 1991] [Johns et al 1992b 1993a] [Oostra et al 1994] [Riordan-Eva et al 1995]. Statistically meaningful comparisons between these groups are difficult due to small numbers and bias of ascertainment; however, patients in all of these groups appear similar with regard to several features.
^ Men are more frequently affected with visual loss than women, comprising 80-90% of case series [Newman et al 1991] [Oostra et al 1994] [Riordan-Eva et al 1995]. Analysis of 85 LHON families demonstrated no statistically significant differences in ratios of affected males to affected females with respect to mutation [Harding et al 1995]. With the exclusion of index cases and sibships less than 50 years old, the best estimate of recurrence risk is 30% to brothers and 8% to sisters of index cases. Affected females are more likely to have affected children, particularly daughters, than unaffected female carriers [Harding et al 1995]. These data suggest the possibility of an X-linked susceptibility locus (see below).
^ The onset of visual loss typically occurs between the ages of 15 and 35 years in most pedigrees. However, molecularly confirmed LHON has been reported in patients as young as 5 and as old as 80 [Newman 1997]. This broad range of ages may occur even within the same pedigree. There are no differences in the age of onset between different mutation groups and be tween secondary and index cases. The age of onset in females is slightly later than in males [Harding et al 1995].
^ Vision loss is, typically painless but may be associated with headache, Uhthoff's symptom (transient worsening with warmth or exercise), eye discomfort, photopsias, limb parasthesias, and dizziness [Newman et al 1991] [Riordan-Eva et al 1995]. Simultaneous, bilateral vision loss is reported in approximately 50% of cases. In eyes with sequential loss, the average interval to involvement of the second eye is 3 months but may rarely remain monocular up to 16 years of follow-up [Nikoskelainen et al 1996]. The vision loss typically reaches its nadir within 2 months but may be slowly progressive over a period of greater than 8 weeks. Visual acuity typically deteriorates to worse than 20 /200 but may range from 20/20 to no light perception. Associated with vision loss is progressive red-green dyschromatopsia. Pupillary light responses are relatively preserved in comparison with those in patients with other optic neuropathies [Wakakura and Yokoe 1995]. Visual field defects are typically central or cecocentral absolute scotomas surrounded by a narrow rim of relative scotoma. The classic fundus appearance of circumpapillary telangiectatic microangiopathy, swelling of the nerve fiber layer around the disc, and absence of leakage from the disc on fluorescein angiography [Smith et al 1973] [Nikoskelainen et al 1982b, 1984b]] may be observed in 50% to 60% of affected patients [Newman et al 1991] [Riordan-Eva et al 1995] as well as in "presymptomatic" cases and asymptomatic maternal relatives [Nikoskelainen et al 1982a, 1984b]. With time, the hyperemia and peripapillary nerve fiber layer swelling resolve, leaving temporal pallor and papillomacular nerve fiber layer dropout.
^ Most patients suffer permanent, profound vision loss and do not experience further insults. However, even after a period of stability lasting up to several years, some patients may experience recovery of excellent vision in one or both eyes [Stone et al 1992]. These patients may have a gradual clearing of their central vision or the sudden opening of a few degrees within the central scotoma resulting in a "fenestrated scotoma" [Mackey 1994]. Color vision may likewise improve [Nikoskelainen et al 1996]. Younger patients have the best prognosis for visual recovery [Mackey and Howell 1992] [Riordan-Eva et al 1995]. The LHON phenotype appears to be uniform with respect to mutation except in the rates of spontaneous recovery. The 14484 mutation carries the best prognosis for recovery with estimated rates as high as 50% [Johns et al 1993a]. The 11778 mutation carries the worst prognosis for recovery with rates estimated at 4k [Newman et al 1991] [Stone et al 1992]. Nikoskelainen et al.  emphasized that 23% of 106 affected eyes had a favorable outcome with a visual acuity better than or equal to 20/50.
^ The use of molecular diagnosis in patients with unexplained bilateral optic neuropathy without the "classic" LHON presentation has expanded the LHON phenotype. These "atypical" cases have been outlined by Nikoskelainen et al . Some patients may present with a subclinical bilateral optic atrophy with a favorable visual outcome. Others may present with a chronic slowly progressive course without an acute phase. These presentations comprise a minority of cases.
^ In most patients with LHON, vision loss is the only clinical manifestation. Some patients may have cardiac conduction abnormalities including preexcitation syndromes, such as Wolf- Parkinson-White and Lown-Ganong- Levine [Nikoskelainen et al 1985, 1994]], or prolongation of the corrected QT interval [Ortiz et al 1992]. Palpitations, syncope, and sudden death may occur in these patients [Nikoskelainen et al 1985, 1994] [Bower et al 1992]. Hearing loss and skeletal abnormalities such as thoracic kyphosis have been reported [Wallace et al 1970] [Mackey 1994] [Nikoskelainen et al 1995]. Minor neurologic symptoms may be present in some patients, including tremor, mild cerebellar ataxia, pathologic reflexes and sensory neuropathy [van Senus 1963] [Wilson 1963] [Funakawa et al 1995] [Nikoskelainen et al 1995]. More severe neurologic symptoms, including a multiple sclerosis (MS)-like syndrome (see below), have been reported in some pedigrees [Wallace 1970]. Those pedigrees in which LHON-like optic neuropathy occurs along with more severe neurologic symptoms have been designated Leber's "plus" [Newman 1993]. Additional mitochondrial point mutations have been identified in some Leber's "plus" pedigrees [Howell et al 1991b] [Jun et al 1994] [Shoffner et al 1995]. In a large Australian pedigree, designated Queensland 1, in which LHON was associated with juvenile encephalomyelopathy, ataxia, spasticity, and posterior column signs, a mutation at mtDNA position 4160 of the NDI gene was found in association with the mtDNA 14484 mutation [Howell et al 1991b]. Three pedigrees in whom optic atrophy was associated with dystonia have been associated with a complex I mutation involving the ND6 subunit at mtDNA position 14,459 [Jun et al 1994] [Shoffner et al 1995].
^ Other clinical studies have helped to characterize the LHON phenotype but are of limited diagnostic usefulness. Fluorescein angiography demonstrates a lack of leakage at the optic nerve head despite swelling [Smith et al 1973] [Nikoskelainen et al 1984b]. Pattern-reversal visual evoked potentials (VEPS) may show absent or prolonged latencies and decreased amplitudes [Newman et al 1991] [Riordan-Eva et al 1995]. Flash electroretinograms are typically normal in affected patients although occasional patients have abnormal scotopic function or b wave attentuation [Newman et al 1991] [Riordan-Eva et al 1995]. Brainstem auditory evoked potentials (BAEPS) may be nonspecifically abnormal in affected patients [Mondelli et al 1990]. BAEPs and VEPs may be abnormal in asymptomatic maternal relatives as well [Mondelli et al 1991]. Electroencephalograms are normal [Newman et al 1991]. Cerebrospinal fluid analysis is typically normal except in those patients with a MS syndrome [Newman et al 1991] [Riordan-Eva et al 1995]. Similarly, brain CT and MRI are normal except in individuals with a MS-like syndrome [Harding et al 1992] or dystonia [Shoffner et al 1995]. In vivo phosphorus magnetic resonance spectroscopy has demonstrated defective brain and muscle metabolism in 11778 LHON patients [Cortelli et al 1991] and asymptomatic carriers [Barbirolo et al 1995].
^ The availability of molecular diagnostic testing has aided the clinical diagnosis of LHON. Bilateral optic neuropathies presumed secondary to demyelinating disease, glaucoma, or malnutrition have been investigated for the presence of mtDNA mutations [Harding et al 1992] [Cullom et al 1993] [Hirano et al 1994] [Rizzo 1995] [Brierly et al 1996]. In some cases, patients with actual LHON had been previously misdiagnosed. In others, it is possible that the pathogenesis of the disease might involve mitochondrial energy production such that mtDNA mutations might influence the disease process.
^ Patients with primary LHON mutations may present with a MS-like syndrome including cerebrospinal fluid lymphocytic pleocytosis with oligoclonal bands and multiple white matter lesions on MRI [Harding et al 1992] [Flanigan and Johns 1993] [Olsen et al 1995]. Harding et al  proposed that the optic nerve damage in these patients could be immunologically mediated and that mitochondrial genes might contribute to MS susceptibility. However, no association was found between LHON and HLA-DR genotype [Govan et al 1994]. Furthermore, testing of large groups of MS patients has found no association with the 11778 mtDNA mutation in Japan or the 3460 and 11778 mt DNA mutations in England [Kellar-Wood et al 1994] [Nishimura et al 1995]. It may be that coincidental demyelinating disease in a patient harboring a primary LHON mutation can cause profound visual loss rather than typical optic neuritis (Mackey, personal communication).
^ Some atypical patients with LHON may have a slowly progressive course [Nikoskelainen et al 1996]. We and others have observed patients in whom LHON has been confused with low-tension glaucoma [Lauer et al 1985]. Glaucoma, which is characterized by insidious visual field loss and optic nerve atrophy with characteristic cupping, is most commonly associated with raised intraocular pressure. However, one-third of patients with glaucomatous optic neuropathy have a normal intraocular pressure [Klein et al 1992]. Some of these patients may be unrecognized cases of LHON. In one study, cupping of the optic nerve was noted in LHON [Ortiz et al 1992]. Alternatively, others have suggested that factors other than intraocular pressure must play a role in the optic nerve damage in low-tension glaucoma patients, perhaps an underlying mitochondrial dysfunction. Brierly et al.  investigated a group of eight low-tension glaucoma patients for the possibility of a systemic defect in mitochondrial function. These patients had normal oxidative phosphorylation assessed from skeletal muscle biopsies, and they lacked all of the primary LHON mutations. Although the results of this study demonstrated no systemic defect in mitochondrial function in low tension glaucoma, optic nerve mitochondrial function could be compromised in these patients by local factors [Brierly et al 1996].
^ The theory that LHON patients must excede a tissue-specific energy utilization threshold to manifest disease has led some to conclude that malnutrition and envirornmental toxins may play a role in the development of vision loss in susceptible patients. In clinical series, the prevalence of alcohol consumption ranges from 14% to 67% and for tobacco consumption from 46% to 75% [Newman et al 1991] [Johns et al 1992b, 1993a] [Riordan-Eva et al 1995]. A series of patients diagnosed with tobacco-alcohol amblyopia was subsequently determined to have LHON by molecular genetic testing [Cullom et al 1993]. Monozygotic twins who were discordant for vision loss associated with the mtDNA 11778 mutation have been reported [Newman et al 1991] [Johns et al 1993b]. Anecdotal reports exist as to the presence of a traumatic or metabolic insult preceding vision loss [Du-Bois et al 1992] [Johns et al 1992b, 1993a]. Rizzo  presented a patient with bilateral optic neuropathy who had vitamin B12 deficiency and the mtDNA 1448j mutation in whom vision improved to 20/20 following treatment. In contrast to the above reports which suggest a role for epigenetic risk factors in vision loss, wide- spread nutritional deficiency in Cuba did not appear to increase the risk of vision loss in a large pedigree harboring the mtDNA 11778 mutation [Newman et al 1994]. Monozygotic twins concordant for vision loss have also been reported [Nikoskelainen et al 1987] [Harding et al 1995]. No systematic twin studies or statistical analysis of alcohol consumption, tobacco smoking, and enviromnental factors as a risk factor for vision loss in susceptible patients have been performed. However, most clinicians recommend that their patients refrain from alcohol and tobacco consumption.
^ Neuropathologic studies of LHON have only been performed on tissues long after the acute injury. These studies have demonstrated atrophy of the optic nerve, nerve fiber, and ganglion cell layers [Wilson 1963] [Adams et al 1966] [Kwittken and Barset 1958] [Bruyn et al 1992] [Kerrison et al 1995]. Although several ofthese studies have reported more wide spread neuropathologic changes including atrophy of the posterior funiculi, corticospinal tracts, striatum, putamen, lateral caudate, and substantia nigra, these patients had Leber's "plus" rather than a clinical disorder limited to the optic nerves, and these studies were performed prior to molecular testing. Whether patients with isolated optic atrophy have more widespread neuropathologic abnormalities is not known [Kerrison et al 1995]. Electron microscopy has demonstrated electron-dense calcium mitochondrial inclusions within ganglion cells in a patient from the Queensland 1 pedigree with the combined mtDNA 4160 and 14484 mutations [Kerrison et al 1995]. Similar inclusions were not observed in a study of a patient with the mtDNA 11778 mutation [Sadun et al 1996]. Several ultrastructural studies of muscle have demonstrated sub-sarcolemmal collection and enlargement of mitochondria, proliferation of cristae, and paracrystalline inclusions [Sadun et al 1994] [Nikoskelainen et al 1984a] [Federico et al 1988] while others have failed to find abnormalities [Novtny et al 1986].
^ While defects in oxidative phosphorylation has been demonstrated by in vivo phosphorus magnetic resonance spectroscopy and in vitro muscle and blood samples [Parker et al 1989] [Larsson et al 1991] [Majander et al 1991] [Toscano et al 1992] [Cortelli et al 1991], how mitochondrial mutations manifest the LHON phenotype is the focus of ongoing study. No animal models of the disease are available. Questions regarding disease pathogenesis are intrinsically related to the issue of disease penetrance. Specifically, why do some offspring not develop vision loss despite harboring a pathogenic mutation and why is a disproportionate number of males affected? Factors proposed to influence disease penetrance include heteroplasmy, an X-linked vision loss susceptibility locus, environmental factors, and secondary mitochondrial mutations. While the influence of environmental factors is discussed above, the significance of secondary mutations is discussed in another article in this issue.
^ Heteroplasmy is a term used to describe the coexistence of mutant and normal mtDNA within the same cell. At each division, a cell's population of mitochondria may drift towards pure normal, pure mutant or remain mixed. The degree of heteroplasmy may differ among tissues [Lott et al 1990]. It has been suggested that a heteroplasmic individual may have a lower risk of vision loss within a pedigree due to a protective effect of normal mitochondria. Heteroplasmy is assayed by densitometry of restriction digests, single strand conformation polymorphism, and counting the proportion of mutant and normal subclones of polymerase chain-reaction (PCR)-derived DNA from the white blood cell (WBC) fraction of whole blood [Howell et al 1991b] [Smith et al 1993] [Mashima et al 1995]. The proportion of mutant DNA in the optic nerve has been determined in two LHON cases. In a patient from the Queensland 1 pedigree in whom all members tested were homoplasmic for the 4160 and 14484 mutations, all clones derived from formalin-fixed optic nerve tissue contained both mutations [Kerrison et al 1995]]. In another patient heteroplasmic for the 11778 mutation in blood, all optic nerve and refinal clones were mutant [Howell et al 1994b]. No studies on optic nerve or retina from asymptomatic patients at risk for vision loss have been performed.
^ Large reviews of molecularly confirmed LHON patients found the incidence of heteroplasmy in blood to be low [Newman et al 1991] [Harding et al 1995]. Evaluation of 75 LHON patients with the 11778 mutation and 101 asymptomatic family members demonstrated a higher prevalence of heteroplasmy in nonaffected individuals [Smith et al 1993]. This was not statistically significant as the overall incidence of heteroplasmy was low. In addition, heteroplasmic patients with vision loss were phenotypically no different from homoplasmic patients. In another study, heteroplasmy was detected in 4% of 124 affected-patients and 13.6% of 140 unaffected matrilineal relatives [Harding et al 1995] . Therefore, heteroplasmy, as assessed in the WBC fraction of whole blood, may have a protective effect in some family members, but the overall frequency is low. It cannot fully explain the differences in disease penetrance among family members.
^ While secondary mitochondrial mutations may potentially influence disease expression or penetrance, nuclear-encoded factors may modify disease penentrance as well. The male predominance in LHON has prompted investigators to propose a two-locus mitochondrial and X chromosome- linked nuclear gene model of inheritance, taking into account X-chromosome inactivation [Bu and Rotter 1991]. Segregation analysis has demonstrated that the inheritance of LHON is consistent with this model [Bu and Rotter 1991] [Nakamura et al 1993]. Bu and Rotter evaluated 31 published pedigrees and estimated a 40% prevalence of homozygosity among affected females, penetrance in heterozygous females of 0.11 due to X-chromosome inactivation, and an X-linked gene frequency of 0.08 [Bu and Rotter 1991]. Similar analysis of Japanese pedigrees estimated an X-linked gene frequency 0.10 and a penetrance of 0.196 among heterozygous females [Nakamura et al., 1993]. The difference in estimated penetrance among heterozygous females was attributed to ethnicity [Nakamura et al 1993]. Analysis of 85 molecularly confirmed LHON pedigrees was consistent with the model of Bu and Rotter [Harding et al 1995].
^ Despite the results of segregation analysis, linkage analysis with X-chromosome markers have been unsuccessful. Early linkage studies of LHON assumed simple X-chromosome inheritance and found no linkage to a panel of X-chromosome markers [Chen et al 1989]. Initial evaluation of several Finnish families linked LHON to a locus on the short arm of chromosome X (DXS7) with a maximum lod score of 2.48 at a recombination fraction of 0 [Vilkki et al 1991]. A lod score above 2 is considered significant for X-linked disorders. However, re-evaluation of this data set after revision of pedigrees, use of stricter liability class criteria, and separation of families according to mtDNA mutations failed to demonstrate linkage [Juvonen et al 1993]. Two other studies failed to demonstrate linkage to X chromosomal markers as well [Sweeney et al 1992] [Carvalho et al 1992]. One possible explanation for the inability to demonstrate an X-linked locus is the incorrect estimation of penetrance in heterozygous females. All studies estimated the penetrance in heterozygous females of 0.01 in contrast to the estimate of 0.11 by Bu and Rotter [Juvonen 1993] [Sweeney et al 1992] [Carvalho et al 1992]. We agree with Nikoskelainen et al.  that the X-linked hypothesis merits further investigation.
^ In view of the possibility of spontaneous visual recovery in LHON, reports of effective treatment must be interpreted with caution. Present treatment regimens are designed to increase mitochondrial energy production. Agents include naturally occuring cofactors in mitochondrial metabolism and anti-oxidants: coenzyme Q10, succinate, idebenone, vitamin K, vitamin K3, vitamin C, thiamine, and vitamin B2. Limited initial experience with coenzyme Q and succinate in affected patients has been disappointing. At this point, no therapy has been consistently demonstrated to benefit patients with vision loss or to prevent vision loss among their asymptomatic maternal relatives.
^ Point mutations in the mitochondrial genome involving various subunits of Complex I of the respiratory chain are necessary for the bilateral loss of central vision seen in LHON, but other factors play a role in disease expression and penetrance. Molecular genetic testing has expanded the clinical spectrum of LHON. Patients may present with subclinical vision loss, progressive vision loss, and subacute vision loss with or without recovery. Age of onset may vary from 5 to 80 years. Factors proposed to influence the risk of vision loss in mutation harboring pedigrees are both genetic and epigenetic: an X-linked factor, secondary mitochondrial mutations, heteroplasmy, nutritional factors, metabolic disease, and toxic exposures. The discovery of the Wallace mutation has inspired considerable research into LHON. As with other genetic disorders, the challenge remains to understand the pathophysiology linking the genetic defect with the patients' clinical manifestations.
Supported in part by a departmental grant (Ophthalmology, Emory University School of Medicine) from Research to Prevent Blindness, Inc., N.Y., N.Y.
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^ Nancy J. Newman, M.D., is the Director of the Neuro-ophthalmology Unit at the Emory Eye Center; Associate Professor of Ophthalmology and Neurology; and Instructor in Neurosurgery at the Emory University School of Medicine, and lecturer in Ophthalmology at Harvard Medical School. After graduating summa cum laude from Princeton University in 1978, she obtained her master's degree in art history from the Courtauld Institute of Art, University of London in 1980 and her medical degree from Harvard Medical School in 1984. Her postgraduate training in neurology and neuro-ophthalmology was at the Massachusetts General Hospital and the Massachusetts Eye and Ear Infirmary. She is on the editorial board of the American Journal of Ophthalmology, and she is currently coediting the fifth edition of Walsh and Hoyt's Clinical Neuro-Ophthalmology. Dr. Newman's clinical and research interests include diseases of the optic nerve and mitochondrial dysfunction.
^ John B. Kerrison, M.D., is a resident In ophthalmology at the Wilmer Ophthalmological Institute, Johns Hopkins Hospital. He graduated summa cum laude from both the Citadel in 1987 and Emory University School of Medicine In 1992. He completed a medical internship at Brigham and Women's Hospital in Boston. He will be pursuing further postgraduate work in neuro ophthalmology at Emory and as assistant chief of service at Wilmer. His research interests include the clinical aspects and molecular genetics of neuro-ophthalmic disorders.
Contract grant sponsor: Research to Prevent Blindness, Inc., N.Y., N.Y.
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